The present invention relates to an improved and industrially advantageous process for the preparation of N-(5-methylnicotinoyl)-4-hydroxypiperidine of Formula I: 
This compound is a key intermediate for the synthesis of rupatadine, a potent dual antagonist of histamine and platelet-activating factor (PAF).
Chemically, rupatadine is 8-chloro-11-[1-[(5-methyl-3-pyridyl)methyl]-piperidin-4-ylidene]-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine having Formula II 
This compound is known in the literature as UR-12592 and is known from Spanish Patent No. 2,042,421 (U.S. Pat. No. 5,407,941 and European Patent No. 577957 are its equivalents in United States and Europe, respectively) assigned to Uriach of Spain. Rupatadine fumarate is a potent dual antagonist of histamine and PAF, with good activity and long duration of action when given by oral route. General pharmacology and toxicity studies reveal a good safety profile. Although compounds with either potent antihistamine properties or PAF antagonist activity are available, rupatadine fumarate possesses a unique profile as it combines both activities with a high level of potency. This dual activity is an advantage over other drugs in the treatment of clinical conditions such as allergic rhinitis, urticaria, atopic eczema or asthma.
A previously known method for the synthesis of the intermediate N-(5-methylnicotinoyl)-4-hydroxy piperidine of Formula I was reported in Spanish Patent No. 2,120,899 assigned to Uriach which involves the reaction of 5-methylnicotinic acid of Formula III 
in the presence of 1,3-dicyclohexylcarbodiimide (DCC) and 1-hydroxybenzotriazole hydrate (HOBT) for 18 hours at room temperature.
The above mentioned method described in the prior art for the manufacture of the desired compound of Formula I suffers from the following limitations:
The process requires commercially limited available and costly raw materials such as 1,3-dicyclohexylcarbodiimide (DCC) and 1-hydroxybenzotriazole hydrate (HOBT).
The process generates a lot of effluent waste such as dicyclohexyl urea and hence is not eco-friendly.
Dicyclohexyl urea generated during the reaction can not be easily removed during the work up at large scale and repeated purification of crude and impure N-(5-methylnicotinoyl)-4-hydroxypiperidine leads to overall loss of yield and makes this process less economically viable.
In order to obtain rupatadine in pure form it is necessary to employ a starting material of suitable purity.
It is an object of the present invention to solve the problems, associated with the prior art and to provide an efficient method for the preparation of N-(5-methylnicotinoyl)-4-hydroxypiperidine of Formula I (as shown in the accompanied drawings). The product obtained by the process of the present invention would be highly useful as a starting material for the preparation of pure rupatadine.
More particularly, the present invention relates to a process for the preparation of N-(5-methylnicotinoyl)-4-hydroxypiperidine of Formula I (as shown in the accompanied drawings) comprising reacting 5-methylnicotinic acid of Formula III with alkyl chloroformate or pivaloyl chloride to give mixed anhydride of Formula IV 
wherein R is alkyl or substituted alkyl preferably methyl, ethyl or tertiary butyl, in a suitable solvent in the presence of an organic base, which on further reaction with 4-hydroxypiperidine of Formula V 
affords the desired product of Formula I.
The alkyl chloroformate is selected from the group consisting of methyl chloroformate, ethyl chloroformate and butyl chloroformate, preferably methyl chloroformate. The alkyl chloroformate or pivaloyl chloride is suitably used in an amount of 1.0 to 2.0 molar equivalents of compound of Formula II, and preferably in an amount of 1.1 to 1.5 molar equivalents.
The term xe2x80x9csuitable solventxe2x80x9d includes chlorinated solvents, aromatic solvents, ethers, esters and mixture(s) thereof. Preferably, the solvent may be selected from the group consisting of dichloromethane, chloroform, toluene, tetrahydrofuran, ethyl acetate and mixture(s) thereof. The solvent is suitably used in an amount of 5 to 20 times of weight of the compound of Formula II, and preferably, in an amount 5 to 10 times.
The suitable organic base is selected from the group comprising triethylamine, trimethylamine, picolines, pyridine, pyridine derivatives, morpholine and morpholine derivatives. The organic base is suitably used in an amount of 1.0 to 2.0 molar equivalents of the compound of Formula III and preferably in an amount of 1.1 to 1.5 molar equivalents.
The reaction of mixed anhydride of Formula IV (wherein R is same as defined earlier) with 4-hydroxy peperidine of Formula V is carried out at a selected temperature range of xe2x88x9240xc2x0 C. to 10xc2x0 C. preferably at xe2x88x9215 to 10xc2x0 C. during a period of 3 hours to several hours. The desired compound N-(5-methylnicotinoyl)-4-hydroxypiperidine of Formula I is isolated by suitable aqueous basic work up.
Suitable aqueous basic work-up involves the adjustment of pH with a base and extraction with organic solvents. Bases may include sodium or potassium hydroxide, sodium hydroxide being the preferred base.
Any organic solvent may be used for extraction and such solvents are known to a person of ordinary skill in the art and include water-immiscible and partially miscible solvents, such as chloroform, dichloromethane, 1,2-dichloroethane, hexanes, cyclohexane, toluene, methyl or ethyl acetate and the like.
The product may be obtained by reducing the volume of organic solvent containing the desired compound by evaporation or evaporation under vacuum, adding a miscible polar solvent and precipitating the desired product by addition of an anti-solvent. Polar solvent may be selected from a group consisting of a lower alkanol, ketones, esters and mixtures thereof. Preferably, the solvent may be selected from the group consisting of methanol, ethanol, acetone, ethyl acetate and mixture(s) thereof.
Suitable anti-solvents include alkanes, mixture of alkanes, such as hexane, cyclohexane or cyclopentane or ethers, such as isopropylether, or aromatic hydrocarbons, such as benzene or toluene. The polar solvent and an anti-solvent should be at least partially miscible and preferably completely miscible.